Diacylglycerol Kinase ? Limits Cytokine-dependent Expansion of CD8⁺ T Cells with Broad Antitumor Capacity.

ABSTRACT: Interleukin-2 and -15 drive expansion/differentiation of cytotoxic CD8⁺ T cells that eliminate targets via antigen-independent killing. This property is clinically relevant for the improvement of T cell-based antitumor therapies. Diacylglycerol kinase ? and ? (DGK?/?) metabolize the diacylglycerol generated following antigen recognition by T lymphocytes. Enhanced expression of these two lipid kinases in tumor-infiltrating CD8⁺ T cells promotes a hyporesponsive state that contributes to tumor immune escape. Inhibition of these two enzymes might thus be of interest for potentiating conventional antigen-directed tumor elimination. In this study, we sought to characterize the contribution of DGK? and ? to antigen-independent cytotoxic functions of CD8⁺ T cells. Analysis of DGK?-deficient mice showed an increase in bystander memory-like CD8⁺ T cell populations not observed in DGK?-deficient mice. We demonstrate that DGK? limits cytokine responses in an antigen-independent manner. Cytokine-specific expansion of DGK?-deficient CD8⁺ T cells promoted enhanced differentiation of innate-like cytotoxic cells in vitro, and correlated with the more potent in vivo anti-tumor responses of DGK?-deficient mice engrafted with the murine A20 lymphoma. Our studies reveal a isoform-specific function for DGK? downstream of IL-2/IL-15-mediated expansion of innate-like cytotoxic T cells, Pharmacological manipulation of DGK? activity is of therapeutic interest for cytokine-directed anti-tumor treatments.

SUBMITTER: Andrada E 

PROVIDER: S-EPMC5440620 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature